Topical compositions comprising bimatoprost and methods for stimulating hair growth therewith

ABSTRACT

Methods and compositions for stimulating the growth of hair are disclosed wherein said compositions include a cyclopentane heptanoic acid, 2-cycloalkyl or arylalkyl compound represented by the formula I 
     
       
         
         
             
             
         
       
     
     wherein the dashed bonds represent the presence or absence of a double bond which can be in the cis or trans configuration and A, B, Z, X, R 1  and R 2  are as defined in the specification and a penetration enhancer. Such compositions are used in stimulating hair growth of human or non-human animals.

RELATED APPLICATION

This application is a continuation of U.S. application Ser. No.16/352,644, filed Mar. 13, 2019, which is a continuation of U.S.application Ser. No. 15/815,182, filed Nov. 16, 2017, and now abandoned,which is a continuation of U.S. application Ser. No. 14/829,957, filedAug. 19, 2015, now U.S. Pat. No. 9,849,140, issued Dec. 26, 2017, whichis a continuation of U.S. application Ser. No. 14/175,972 filed Feb. 7,2014, now U.S. Pat. No. 9,149,484, issued Oct. 6, 2015, which in turnclaims priority to U.S. Provisional Application Ser. No. 61/783,962,filed on Mar. 14, 2013, which is also a continuation-in-part of U.S.application Ser. No. 14/163,954 filed Jan. 24, 2014, now U.S. Pat. No.9,138,840, issued Sep. 22, 2015, which is a continuation of U.S.application Ser. No. 12/940,711, filed Nov. 5, 2010, now abandoned,which claims priority to U.S. Provisional Application Ser. No.61/259,368, filed on Nov. 9, 2009, the disclosures of which are herebyincorporated herein by reference.

FIELD OF THE INVENTION

Disclosed herein are topical compositions and methods for stimulatingthe growth of hair and treating disorders resulting in hair loss whereinsaid compositions include a cyclopentane heptanoic acid, 2-cycloalkyl orarylalkyl compound represented by the formula I:

wherein the dashed bonds represent the presence or absence of a doublebond which can be in the cis or trans configuration and A, B, Z, X, R₁and R₂ are as defined in the specification and a penetration enhancer.Such compositions are used in stimulating hair growth of human ornon-human animals.

BACKGROUND OF THE INVENTION

Dermatologists recognize many different types of hair loss, the mostcommon being “alopecia” or “baldness” wherein humans (mostly males)begin losing scalp hair at the temples and on the crown of their head.However, hair loss may be due to many other disorders.

Hair loss is often accompanied by a change in the hair growth cycle. Allmammalian hair passes through a life cycle that includes the anagenphase, the catagen phase and the telogen phase. The anagen phase is theperiod of active hair growth. In the scalp, this phase lasts from 3-5years. The catagen phase is a short 1-2 week transitional phase betweenthe anagen phase and the telogen phase. The final telogen phase isconsidered a “resting phase” where all growth ceases. This phase is alsorelatively short-lived lasting about 3-4 months before the hair is shedand a new one begins to grow. With the onset of baldness, a successivelygreater proportion of hairs are in the telogen phase withcorrespondingly fewer in the active growth anagen phase.

Additionally, different types of hair exist including terminal hairs,vellus hairs and modified terminal hairs. Terminal hairs are coarse,pigmented, long hairs in which the bulb of the hair follicle is seateddeep in the dermis. Vellus hairs, on the other hand, are fine, thin,non-pigmented short hairs in which the hair bulb is locatedsuperficially in the dermis. Modified terminal hairs are seen in eyelashes and eye brows. As alopecia progresses, a transition takes placewherein the hairs themselves change from the terminal to the vellustype. Accordingly, alopecia (baldness) also includes a deficiency interminal hairs.

One non-drug treatment for alopecia is hair transplantation. Plugs ofskin containing hair are transplanted from areas of the scalp where hairis growing to bald areas. This approach can be reasonably successful,however it is costly, time-consuming and painful. Other non-drug relatedapproaches to treating alopecia include ultra-violet radiation, massage,psychiatric treatment and exercise therapy. None of these approaches,however, have been generally accepted as effective. Even such things asrevascularization surgery or acupuncture have shown little, if any,effect.

SUMMARY OF THE INVENTION

Compositions and methods are disclosed herein for topical application ofan effective amount of at least one penetration enhancer andcyclopentane heptanoic acid, 2-cycloalkyl or arylalkyl compoundrepresented by the formula I:

wherein the dashed bonds represent the presence or absence of a doublebond which can be in the cis or trans configuration, A is an alkylene oralkenylene radical having from two to six carbon atoms, which radicalcan be interrupted by one or more oxo radicals and substituted with oneor more hydroxy, oxo, alkyloxy or alkylcarboxy groups wherein the alkylradical comprises from one to six carbon atoms; B is a cycloalkylradical having from three to seven carbon atoms, or an aryl radical,selected from the group consisting of hydrogen, a lower alkyl radicalhaving from four to ten carbon atoms wherein the heteroatom is selectedfrom the group consisting of nitrogen, oxygen and sulfur atoms; X is—N(R₄)₂ wherein R₄ is selected from the group consisting of hydrogen, alower alkyl radical having from one to six carbon atoms,

wherein R₅ is a lower alkyl radical having from one to six carbon atoms;Z is ═O; one of R₁ and R₂ is ═O, —OH or a —O(CO)R₆ group, and the otherone is —OH or —O(CO)R₆, or R₁ is ═O and R₂ is H, wherein R₆ is asaturated or unsaturated acyclic hydrocarbon group having from 1 toabout 20 carbon atoms, or—(CH₂)_(m)R₇ wherein m is 0 or an integer of from 1 to 10, and R₇ iscycloalkyl radical, having from three to seven carbon atoms, or ahydrocarbyl aryl or heteroaryl radical, as defined above in free form ora pharmaceutically acceptable salt thereof, in association with apenetration enhancer in particular formulations adapted for topicalapplication to mammalian skin.

In one embodiment, the cyclopentane heptanoic acid, 2-cycloalkyl orarylalkyl compound represented by the formula I is the compoundbimatoprost.

Another embodiment includes a composition comprising bimatoprost at aconcentration of about 0.001-1.5% w/w, from 0.01-1.0% w/w, from0.02-1.0% w/w, 0.03 to about 1.0% w/w, 0.03 to 0.9% w/w, 0.04 to 0.8%w/w, 0.05-0.7% w/w, 0.06%-0.6% w/w, 0.07%-0.5% w/w, 0.08-0.4% w/w,0.09-0.3% w/w, 0.03%-5% w/w, 0.3%-3% w/w, 1%-3% w/w, 0.1% w/w, 0.15%w/w, 0.2% w/w, 0.3% w/w, 0.4% w/w, 0.5% w/w, 0.6% w/w, 0.7% w/w, 0.8%w/w, 0.9% w/w, 1.0% w/w, 1.5% w/w, 2% w/w, 3% w/w, 3.5% w/w, 4% w/w, 5%w/w, 5.5% w/w, 6% w/w, 6.5% w/w, 7% w/w, 8% w/w, 9% w/w, and 10% w/w.The preferred bimatoprost concentration range is about 2-4% w/w, morepreferably about 2.5-3.5% w/w. These preferred bimatoprost concentrationranges allow a surprisingly good balance to be achieved between thewanted pharmacologic effects of the composition and any unwantedside-effects. It had previously been thought that bimatoprostcompositions for stimulating growth of hair should have a much lowerbimatoprost concentration; this has now surprisingly been found not tobe the case.

The following excipients may also be included: Carbomer at aconcentration of about 0.05-1.0% w/w; base at a concentration of about0.01 to about 2.0% w/w; ethanol at a concentration of about 10 to about90% w/w; glycerin at a concentration of about 1.0 to about 20% w/w;diethylene glycol monoethyl ether at a concentration of about 1.0 toabout 50% w/w; polysorbate 20 at a concentration of about 0.1 to about5.0% w/w; polysorbate 40 at a concentration of about 0.1 to about 5.0%w/w; polysorbate 60 at a concentration of about 0.1 to about 5.0% w/w;polysorbate 80 at a concentration of about 0.1 to about 5.0% w/w; PPG-5ceteth-20 at a concentration of about 0.1 to about 5.0% w/w; oleic acidat a concentration of about 0.1 to about 5.0% w/w; isostearylisostearate at a concentration of about 0.1 to about 10% w/w; isopropylmyristate at a concentration of about 0.1 to about 10% w/w; dipropyleneglycol dimethyl ether at a concentration of about 1 to about 50% w/w;diethylene glycol at a concentration of about 1 to about 50% w/w;dipropylene glycol at a concentration of about 1 to about 50% w/w;caprylic/capric at a concentration of about 0.1 to about 10% w/w; benzylalcohol at a concentration of about 0.1 to about 2.0% w/w; silicone at aconcentration of about 0.1 to about 10% w/w; PEG 40 castor oil at aconcentration of about 0.1 to 20% w/w; PEG 35 castor oil at aconcentration of about 0.1 to 20% w/w; oleyl alcohol at a concentrationof about 0.1 to 10% w/w; glyceryl monooleate at a concentration of about0.1 to 10% w/w; and/or water at a concentration of about 0 to about 90%w/w.

Another embodiment includes a composition comprising bimatoprost atabout 0.1% w/w; carbomer at about 0.10% w/w; NaOH at about 0.035% w/w;ethanol at about 15.0% w/w; diethylene glycol monoethyl ether at about10.0% w/w; and water at about 74.8% w/w.

Another embodiment includes a composition comprising bimatoprost atabout 0.1% w/w; carbomer at about 0.15% w/w; triethylamine (TEA) atabout 0.22% w/w; ethanol at about 15.0% w/w; diethylene glycol monoethylether at about 10.0% w/w; polysorbate 20 at about 4.0% w/w; and water atabout 70.5% w/w.

Another embodiment includes a composition comprising bimatoprost atabout 0.1% w/w; carbomer at about 0.125% w/w; TEA at about 0.18% w/w;ethanol at about 30.0% w/w; diethylene glycol monoethyl ether at about20.0% w/w; and water at about 49.59% w/w.

Another embodiment includes a composition comprising bimatoprost atabout 0.1% w/w; carbomer at about 0.10% w/w; TEA at about 0.15% w/w;ethanol at about 30.0% w/w; propylene glycol at about 20% w/w; and waterat about 49.7% w/w.

Another embodiment includes a composition comprising bimatoprost atabout 0.1% w/w; carbomer at about 0.20% w/w; TEA at about 0.22% w/w;ethanol at about 60.0% w/w; glycerin at about 5.0% w/w; and water atabout 34.48% w/w.

Another embodiment includes a composition comprising bimatoprost atabout 0.1% w/w; carbomer at about 0.25% w/w; TEA at about 0.38% w/w;ethanol at about 60.0% w/w; polysorbate 20 at about 4.0% w/w; and waterat about 35.27% w/w.

Another embodiment includes a composition comprising bimatoprost atabout 0.1% w/w; carbomer at about 0.25% w/w; TEA at about 0.38% w/w;ethanol at about 50.0% w/w; diethylene glycol monoethyl ether at about10% w/w; polysorbate 20 at about 4.0% w/w; and water at about 35.27%w/w.

In some embodiments, the composition comprises water, bimatoprost at aconcentration of about 1% w/w to about 4% w/w, preferably about 2-4% w/wand most preferably 2.5-3.5% w/w, and one or more selected from thegroup consisting of: cetostearyl alcohol at a concentration of about0.5% w/w to about 1% w/w, glyceryl mono-oleate at a concentration ofabout 1% w/w to about 3% w/w, preferably about 2% w/w, oleyl alcohol ata concentration of about 1% w/w to about 3% w/w, preferably about 2%w/w, ethanol at a concentration of about 30% w/w to about 75% w/w,propylene glycol at a concentration of about 10% w/w to about 25% w/w,benzyl alcohol at a concentration of about 0.5% w/w to about 2% w/w,preferably about 1% w/w, ultrez at a concentration of about 0.15% w/w,trolamine at a concentration of about 0.16% w/w, and glycerol at aconcentration of about 0.5% w/w to about 10% w/w, preferably 2% w/w.

In some embodiments, the composition comprises water, bimatoprost at aconcentration of about 1-5% w/w, preferably about 2-4% w/w, morepreferably about 2.5-3.5% w/w, the most preferred value being 3% w/w,and one or more selected from the group consisting of: transcutol at aconcentration of about 1% w/w to about 25% w/w, preferably about 10%w/w, propylene glycol at a concentration of about 1 w/w to about 25%w/w, glycerol monooleate at a concentration of about 1% w/w to about 3%w/w, preferably about 2% w/w, oleyl alcohol at a concentration of about1 w/w to about 3% w/w, preferably about 2% w/w, ethanol at aconcentration of about 30% w/w to about 75% w/w, propylene glycol at aconcentration of about 10% w/w to about 25% w/w, benzyl alcohol at aconcentration of about 0.5% w/w to about 2% w/w, preferably about 1%w/w, carbomer ultrez at a concentration of about 0.15% w/w to about 0.2%w/w, triethanolamine at a concentration of about 0.16% w/w, and glycerinat a concentration of about 0.5% w/w to about 10% w/w, preferably 2%w/w.

Some embodiments may also comprise one or more additional ingredients inaddition to those specified in the paragraph above, wherein the one ormore ingredients are selected from the group consisting of linoleic acidat a concentration of about 1% w/w to about 5% w/w, preferably 2% w/w,sodium lauryl sulfate at a concentration between 0.1% w/w to about 0.5%w/w, preferably 0.2% w/w, and docusate sodium at a concentration between0.1% w/w to about 0.5% w/w, preferably 0.2% w/w.

In some embodiments, the composition comprises water, bimatoprost at aconcentration of about 1-5% w/w, preferably about 2-4% w/w, morepreferably about 2.5-3.5% w/w the most preferred value being 3% w/w, andone or more selected from the group consisting of: transcutol at aconcentration of about 1% w/w to about 25% w/w, preferably about 10%w/w, propylene glycol at a concentration of about 1% w/w to about 25%w/w, glycerol monooleate at a concentration of about 1% w/w to about 3%w/w, preferably about 2% w/w, oleic acid at a concentration of about 1%w/w to about 3% w/w, preferably about 2% w/w, linoleic acid at aconcentration of about 1% w/w to about 3% w/w, preferably about 2% w/w,ethanol at a concentration of about 30% w/w to about 75% w/w, propyleneglycol at a concentration of about 10% w/w to about 25% w/w, benzylalcohol at a concentration of about 0.5% w/w to about 2% w/w, preferablyabout 1% w/w, carbomer ultrez at a concentration of about 0.15% w/w toabout 0.2% w/w, triethanolamine at a concentration of about 0.16% w/w,glycerin at a concentration of about 0.5% w/w to about 10% w/w,preferably about 2% w/w, terpinolene at a concentration of about 0.5%w/w to about 5% w/w, preferably about 2% w/w, limonene at aconcentration of about 0.5% w/w to about 5% w/w, preferably about 2%w/w, nerol at a concentration of about 0.5% w/w to about 5% w/w,preferably about 2% w/w, cineol at a concentration of about 0.5% w/w toabout 5% w/w, preferably about 2% w/w, octyl salicylate at aconcentration of about 0.5% w/w to about 5% w/w, preferably about 2%w/w, DMSO at a concentration of about 0.5% w/w to about 5% w/w,preferably about 2% w/w, DDAB at a concentration of about 0.01% w/w toabout 1% w/w, preferably about 0.2% w/w, sodium taurodeoxycholate at aconcentration of about 0.01% w/w to about 5% w/w, preferably about 2%w/w, docusate sodium at a concentration of about 0.01% w/w to about 1%w/w, preferably about 0.2% w/w, Crodamol MM at a concentration of about1% w/w to about 30% w/w, preferably about 25% w/w, polysorbate 80 at aconcentration of about 1% w/w to about 5% w/w, preferably about 2% w/w.,Dow ST-Elastomer 10 at a concentration of about 40% w/w to about 80%w/w, preferably about 73.5% w/w, Dow Silky Wax 10 at a concentration ofabout 1% w/w to about 20% w/w, preferably about 8% w/w, IsopropylMyristate at a concentration of about 1% w/w to about 20% w/w,preferably about 8% w/w.

In some embodiments, the composition comprises water; bimatoprost, forexample at a concentration from about 0.3% w/w to about 5% w/w,preferably about 1-5% w/w or about 2-4% w/w, more preferably about2.5-3.5% w/w the most preferred value being 3% w/w; and one or moreselected from the following: ethanol, for example at a concentrationbetween 0% w/w to about 89% w/w; propylene glycol, for example at aconcentration between 0% w/w to about 89% w/w; diethylene glycolmonoethyl ether, for example at a concentration between 0% w/w to about89% w/w; benzyl alcohol, for example at a concentration between 0% w/wto about 89% w/w; and one or more fatty acids and/or fatty esterexcipients, for example at a concentration between 0% w/w to about 10%w/w. In some embodiments, the fatty acids may include one or more C₈-C₂₈fatty acids, and which may be saturated, monounsaturated, orpolyunsaturated. In some embodiments, a saturated fatty acid may bestearic acid. In some embodiments, a monounsaturated fatty acid may beoleic acid. In some embodiments, a polyunsaturated fatty acid may belinoleic acid. In some embodiments, the fatty ester may one or moreinclude C₈-C₂₈ fatty acids, and which may be saturated, monounsaturated,or polyunsaturated. In some embodiments, a saturated fatty ester may beglyceryl monostearate. In some embodiments, a monounsaturated fattyester may be glyceryl monooleate. In some embodiments, a polyunsaturatedfatty ester may be ethyl ester of linoleic acid.

A preferred composition comprises bimatoprost, oleyl alcohol, ethanoland propylene glycol. Bimatoprost is comprised in an amount of about1-5% w/w, preferably about 2-4% w/w, more preferably about 2.5-3.5% w/wthe most preferred value being 3% w/w. Oleyl alcohol is comprised in anamount of about 1-10% w/w. Ethanol is comprised in an amount of about50-80% w/w. Propylene glycol is comprised in an amount of 15-15% w/w.

Examples of particularly preferred compositions for growing hair bytopical application comprise bimatoprost in free form or apharmaceutically acceptable salt thereof, wherein the bimatoprost iscontained in an amount of about 0.3% w/w to about 4% w/w; at least onefirst compound selected from a fatty acid, fatty acid alcohol and fattyester, wherein said composition is formulated for topical administrationto the skin.

In some embodiments, the first compound is a fatty acid. The fatty acidmay be saturated or unsaturated. In some embodiments, the fatty acid isselected from the group consisting of stearic acid, oleic acid, linoleicacid, and mixtures thereof. In some embodiments, the first compound is afatty ester. The fatty ester may be saturated or unsaturated. The fattyester may be selected from the group consisting of glycerylmonostearate, glyceryl monooleate, and ethyl ester of linoleic acid. Insome embodiments, the composition comprises at least two firstcompounds. The composition may comprise a mixture of at last one fattyacid and at least one fatty ester. The first compound may have 12-24carbon atoms. The composition may further comprise at least one secondcompound selected from the group consisting of ethanol, propyleneglycol, diethylene glycol monoethyl ether, and benzyl alcohol. Thecomposition may further comprise at least one third compound selectedfrom the group consisting of terpenes, occlusive agents, surface activeagents, sulfoxides, cyclic ethers, amides, amines, anddimethylaminopropionic acid derivatives. In some embodiments, theterpene is selected from the group consisting of terpinolene, limonene,nerol, and cineol. In some embodiments, the occlusive agent is selectedfrom the group consisting of silicones, mineral oils, and waterinsoluble polymers. In some embodiments, the surface active agent isselected from the group consisting of polysorbate 20, polysorbate 40,polysorbate 60, polysorbate 80, sodium dodecyl sulfate, sodium laurylsulfate, DMSO, and docusate sodium. In some embodiments, thedimethylaminopropionic acid derivative is 2-dimethylaminopropionic aciddodecyl ester. The composition may comprise bimatoprost in an amount ofabout 1% w/w to about 4% w/w. More preferably, the composition maycomprise bimatoprost in an amount of about 2.5% w/w to about 3.5% w/w.Most preferably, the composition may comprise bimatoprost in an amountof about 3% w/w. In some embodiments, the composition is in the form ofone selected from the group consisting of solutions, gels, ointments,foams, films, liniments, creams, shampoos, lotions, pastes, jellies,sprays and aerosols. In some embodiments, the composition is packaged ina kit with an applicator for application to the skin.

In some preferred embodiments, a method for stimulating hair growthcomprises administering to the skin of a patient an effective amount ofa bimatoprost composition according to any embodiment previouslydescribed, wherein the administration causes increased hair growth. Thecomposition may be applied to the scalp. The composition may be appliedat least once daily. In some embodiments, the composition is applied tothe scalp for treatment of a condition selected from the groupconsisting of alopecia areata, telogen effluvium, anagen effluvium,cicatricial alopecia, scarring alopecia; hair shaft abnormalities,trichorrexis nodosa, loose anagen syndrome, trichotillomania, tractionalopecia; infectious hair disorders, tiniea capitis, sebohorreicdermatitis, follicullitus of the scalp, and androgenetic alopecia. Insome embodiments, wherein the composition is applied to one or both ofthe scalp and the eyebrows for patients experiencing hair loss due tochemotherapy, hormonal imbalance, fungal infection of the scalp,anti-coagulants, medicine for gout, depression, high blood pressure andheart disease.

In one embodiment, a composition for promoting the growth of haircomprises: at least one penetration enhancer; and bimatoprost in freeform or a pharmaceutically acceptable salt thereof, wherein thebimatoprost is contained in an amount of about 1-4% w/w; wherein saidcomposition is formulated for topical administration to the skin. Insome embodiments, the penetration enhancer is selected from one or moreof the group consisting of alcohols, glycols, fatty acids, fatty esters,fatty ethers, occlusive agents, surface active agents,dimethylaminoproprionic acid derivatives, terpenes, sulfoxides, cyclicethers, amides, and amines.

It will of course be understood that the ranges described above, andthroughout this document, are also intended to encompass single valuescontained within these ranges. For example, for a formulation comprisinga particular ingredient in a range between 1-50%, a percentage of 5% or49% is also intended to be disclosed.

The compositions were manufactured using the following generalprocedure. Non-aqueous components (e.g. bimatoprost, ethanol, glycols)were combined in a beaker and stirred using a propeller type overheadmixer until the solution was clear. Water was added to the non-aqueousmixture followed by the addition of the thickening agent. Upondispersion of the thickening agent, a base was added to neutralize thepolymer and thicken the solution into a gel other desired composition.For example, ethanol and bimatoprost were combined in a beaker andstirred using a propeller type overhead mixer until the solution wasclear. This mixture was then added to the non-aqueous ingredients toform a non-aqueous mixture. In a separate vessel the thickening agentwas dispersed in water to form an aqueous mixture, which was then addedto the non-aqueous mixture. Upon mixing of the non-aqueous and aqueousmixtures, a base was added to neutralize the polymer and to thicken thesolution into a gel.

In yet another embodiment, a composition for growing hair by topicalapplication comprises

at least one penetration enhancer comprising oleyl alcohol; andbimatoprost in free form or a pharmaceutically acceptable salt thereof;wherein said composition is formulated for topical administration to theskin.

In some embodiments, the composition comprises from between about 0.3%to about 10% by weight of bimatoprost, preferably about 1-5% w/w orabout 2-4% w/w, more preferably about 2.5-3.5% w/w the most preferredvalue being 3% w/w. In some embodiments, the composition comprises about1% by weight of bimatoprost. In some embodiments, the compositioncomprises about 3% by weight of bimatoprost. The composition maycomprise about 3% by weight of bimatoprost, about 5% by weight of oleylalcohol, about 66% by weight of ethanol, and about 22% by weight ofpropylene glycol. The composition may be in the form of one selectedfrom the group consisting of solutions, gels, ointments, foams, films,liniments, creams, shampoos, lotions, pastes, jellies, sprays andaerosols. The composition may be packaged in a kit with an applicatorfor application to the skin.

In another embodiment, a method for stimulating hair growth comprisesadministering to the skin of a patient an effective amount of abimatoprost composition as described herein, wherein the administrationcauses increased hair growth.

In some embodiments, the composition is applied to the scalp. In someembodiments, the composition is applied at least once daily. Thecomposition may be applied to the scalp for treatment of conditionsselected from the group consisting of alopecia areata, telogeneffluvium, anagen effluvium, cicatricial alopecia, scarring alopecia;hair shaft abnormalities, trichorrexis nodosa, loose anagen syndrome,trichotillomania, traction alopecia; infectious hair disorders, tinieacapitis, sebohorreic dermatitis, follicullitus of the scalp, andandrogenetic alopecia. The composition may be applied to one or both ofthe scalp and the eyebrows for patients experiencing hair loss due tochemotherapy, hormonal imbalance, fungal infection of the scalp,anti-coagulants, medicine for gout, depression, high blood pressure andheart disease.

In some embodiments, a suitable formulation for topical administrationof bimatoprost may comprise one or more of the following ingredientslisted in the table below:

Ingredient Bimatoprost Bimatoprost (% w/w) Function solution 1 solution2 Bimatoprost Active  0.3-6%  0.3-6% Oleyl Alcohol Penetration 00.1-10%  Ethanol enhancer 40-80% 40-80% Propylene 10-30% 10-30% glycolThickener Thickener  0-6%  0-6% Carbopol or other thickeners (Sepineo,cellulose, etc) Triethanolamine Neutralizing QSAD QSAD or other Agentneutralizer as appropriate Purified water Vehicle QS 100%  QS 100% 

DETAILED DESCRIPTION

Bimatoprost is a moderately soluble compound intended for topicaldelivery to the skin to stimulate hair growth. Hair growth includes,without limitation, stimulating the conversion of vellus hair to growthas terminal hair as well as increasing the rate of growth of terminalhair. Embodiments disclosed herein provide formulations of bimatoprostand similar compounds with penetration enhancers. These penetrationenhancers facilitate active component penetration and/or maintenance attheir site of action in the skin. Formulations disclosed herein can beself-preserved or contain an antimicrobial agent such as benzyl alcohol.

In accordance with embodiments disclosed herein, active components arerepresented by

The active components are provided in particular formulations thatinclude penetration enhancers. Some examples of representative compoundsuseful in the practice of embodiments disclosed herein include thecompounds shown in Table 1:

TABLE 1 Representative Compounds cyclopentaneheptenamide-5-cis-2-(3α-hydroxy-5-phenyl-1-trans-pente-nyl)-3,5-dihydroxy, [1_(α),2_(β),3_(α),5_(α)] cyclopentaneN,N-dimethylheptenam-ide-5-cis-2-(3α-hydroxy-5-phenyl-1-trans-penten-yl)-3,5-dihydroxy,[1_(α),2_(β),3_(α),5_(α)] cyclopentaneheptenylamide-5-cis-2-(3α-hydroxy-4-meta-chlorophenoxy-1-trans-pent-enyl)-3,5-dihydroxy, [1_(α),2_(β),3_(α),5_(α)] cyclopentaneheptenylamide-5-cis-2-(3α-hydroxy-4-trifluoromethylphe-noxy-1-trans--pentenyl)-3,5-dihydroxy, [1_(α),2_(β),3_(α),5_(α)]cyclopentane N-isopropyl heptenamide-5-cis-2-(3α-hydroxy-5-phenyl-1-trans-pentenyl)-3,5-dihydroxy, [1_(α),2_(β),3_(α),5_(α)] cyclopentaneN-ethyl heptenamide-5-cis-2-(3α-hydroxy-5-phenyl-1-trans-pentenyl)-3,5-dihydroxy, [1_(α),2_(β),3_(α),5_(α)] cyclopentane N-methylheptenamide-5-cis-2-(3α-hydroxy-5-phenyl-1-trans-pentenyl)-3,5-dihydroxy, [1_(α),2_(β),3_(α),5_(α)] cyclopentaneheptenamide-5-cis-2-(3α-hydroxy-4-meta-chlorophenoxy-1-trans-buteny-l)-3,5-dihydroxy, [1_(α),2_(β),3_(α),5_(α)]

In one embodiment, the compound is a cyclopentane heptanoic acid,2-(phenyl alkyl or phenyloxyalkyl) represented by the formula II:

wherein y is 0 or 1, x is 0 or 1 and x and y are not both 1, Y isselected from the group consisting of alkyl, halo, e.g. fluoro, chloro,etc., nitro, amino, thiol, hydroxy, alkyloxy, alkylcarboxy, halosubstituted alkyl wherein said alkyl radical comprises from one to sixcarbon atoms, etc. and n is 0 or an integer of from 1 to 3 and R₃ is ═O,—OH or —O(CO)R₆ wherein R₆ is as defined above or a pharmaceuticallyacceptable salt thereof.

In another embodiment, the compound is a compound of formula III:

wherein hatched lines indicate α configuration, solid triangles are usedto indicate β configuration. In another embodiment, y is 1 and x is 0and R₁, R₂ and R₃ are hydroxy.

One exemplary active compound is cyclopentane N-ethylheptanamide-5-cis-2-(3α-hydroxy-5-phenyl-1-trans-pentenyl)-3,5-dihy-droxy,[1_(α),2_(β),3_(α),5_(α)], also known as bimatoprost and sold under thename of LUMIGAN® by Allergan, Inc., California, USA. This compound hasthe following structure:

The synthesis of the above compounds has been disclosed in U.S. Pat. No.5,607,978 which is incorporated by reference in its entirety.

The compound will generally range from about 1×10⁻⁷ to about 50% w/w ofthe composition, in one embodiment from about 0.001 to about 50% w/w ofthe composition and in another embodiment from about 0.1 to about 30%w/w of the composition. In some embodiments, a preferred range of theactive compound may be about 0.03% w/w to about 5%, more preferablyabout 0.3% w/w to about 3% w/w, and even more preferably, about 1 w/w toabout 3% w/w. Ranges and percentages within about 0.3% w/w, 0.5% w/w, 1%w/w, 1.5% w/w, 2% w/w, 3% w/w, 3.5% w/w, 4% w/w, 5% w/w, 5.5% w/w, 6%w/w, 6.5% w/w, 7% w/w, 8% w/w, 9% w/w, 10% w/w; 10-50% w/w; about 20-50%w/w; about 30-40% w/w and about 35% are also included.

The pharmaceutical formulations disclosed herein can include one or morepenetration enhancers. The phrase “penetration enhancers” includes anyagent that facilitates the transfer or delivery of active components totheir site of action and/or maintains the active component at their siteof action. Non-limiting examples of classes of appropriate penetrationenhancers include alcohols, glycols, fatty acids, ethers, esters,occlusive agents and surface active agents. Representative andnon-limiting examples of these classes are provided below. It will ofcourse be understood that one or more penetration enhancers or classesthereof may be combined in the various embodiments disclosed herein.

Alcohols include, without limitation, aliphatic and aromatic alcohols,including ethanol, propanol, n-propanol, isopropanol, butyl alcohol,octanol, benzyl alcohol and acetyl alcohol, in one embodiment, asdescribed in U.S. Pat. No. 5,789,244, the entire contents of which areincorporated by reference herein. Fatty alcohols include, for example,saturated and unsaturated fatty alcohols, including for example thosewith C₈-C₂₈ chain length, stearyl alcohol, oleyl alcohol, palmitylalcohol, and lauryl alcohol, and combinations thereof. In someembodiments, oleyl alcohol may be used in a range between about 0.5% w/wto about 50% w/w, preferably between about 1% w/w and about 10% w/w, andeven more preferably between about 3% w/w and about 6% w/w. Percentagesof 1% w/w, 1.5% w/w, 2% w/w, 3% w/w, 3.5% w/w, 4% w/w, 5% w/w, 5.5% w/w,6% w/w, 7% w/w, 8% w/w, 9% w/w, and 10% w/w are also contemplated. Mostpreferably, oleyl alcohol may be present at about 5% w/w.

Glycols include, without limitation, propylene glycol, polyethyleneglycols (including for example polyethylene glycols with a molecularweight from about 300-8000 Daltons), glycol derivatives, and other lowmolecular weight glycols such as glycerol and thioglycerol.

Fatty acids, esters and ethers include, without limitation, saturated,monounsaturated, and polyunsaturated C₈-C₂₈ fatty acids and fattyesters, such as C₄-C₂₀ saturated monocarboxylic and dicarboxylic acids,straight chain fatty acids, stearic acid, oleic acid, linoleic acid,palmitoleic acid, octanoic and decanoic acids, methyl laurate, ethyloleate, polyethylene glycol monolaurate, propylene glycol monolaurate,propylene glycerol dilaurate, glycerol monolaurate, glyceryl monooleate,glyceryl monostearate, ethyl esters of linoleic acid, isopropyln-decanoate, octyldodecyl myristate, diethylene glycol monoethyl ether,diethylene glycol monomethyl ether, Crodamol MM, Isopropyl myristate,and compounds wherein a C₂-C₄ alkane diol or triol is substituted withone or two fatty ether substituents.

Occlusive agents include, without limitation, silicones (including DowST-Elastomer 10, Dow Silky Wax 10), mineral oils and greases, long chainacids, animal fats and greases, vegetable fats and greases, waterinsoluble polymers, paraffin, paraffin oil, liquid paraffin, petrolatum,liquid petrolatum, white petrolatum, yellow petrolatum, microcrystallinewax and ceresin.

Surface active agents include without limitation nonionic, anionic, andcationic agents, and combinations thereof, such as polysorbate 20, 40,60 and 80, TWEEN® (20, 40, 60, 80) and optionally corresponding SPANSeries (20, 40, 60, 80), POLOXAMER® (231, 182, 184), sodium dodecylsulfate (SDS), macrogol 15 hydroxystearate, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer.lecithin, lysolecithin, nonylphenoxypolyoxyethylene,lysophosphatidylcholine, polyethylenglycol 400, polyoxyethylene ethers,polyglycol ether surfactants, sodium laurate, sodium lauryl sulfate,cetyltrimethylammonium bromide, docusate sodium, and benzalkoniumchloride.

Other penetration enhancers that may be useful includedimethylaminoproprionic acid derivatives, such as2-dimethylaminopropionic acid dodecyl ester (DDAIP); terpenes, includingterpinolene, limonene, nerol, cineol; sulfoxides such as DMSO; cyclicethers; amides and amines, such as Didecyldimethylammonium bromide(DDAB), sodium taurodeoxycholate, triethylamine; octyl salicylate, andcombinations thereof.

Additional penetration enhancers will be known to those of ordinaryskill in the art of topical drug delivery, and/or are described in thepertinent texts and literature.

Embodiments disclosed herein can also include viscosity increasingagents. Appropriate agents include, without limitation, methylcellulose,ethyl cellulose, hydroxyethyl cellulose, acrylamide/sodiumacryloyldimethyltaurate copolymer, polyacrylic acid, polyvinyl alcohol,polyvinyl pyrrolidone, hyaluronic acid and chondroitin sulfate.

Certain embodiments disclosed herein can include preservativesincluding, without limitation, phenoxyethanol, benzyl alcohol,benzalkonium chloride, chlorhexidine, chlorobutanol, methyl-, propyl-,or butyl-parahydroxybenzoic acids, phenylmercuric salts including,without limitation, nitrate, chloride, acetate, and borate and betain.

Various other additives may be included in the compositions of thepresent invention in addition to those identified above. These include,but are not limited to, antioxidants, astringents, perfumes, emollients,pigments, dyes, humectants, propellants, and sunscreen agents, as wellas other classes of materials whose presence may be cosmetically,medicinally or otherwise desirable. The compositions and formulationsmay also be taken in conjunction with minoxidil and propecia.

Compositions can also be formulated as “slow-releasing” formulations sothat the activity of active components is sustained for a longer periodof time between treatments.

While particular embodiments disclosed herein can include each of thecomponents discussed above, other particular embodiments can be requiredto be “substantially free” of one or more of these components in variouscombinations. “Substantially free”, as used herein, means that thecomponent is not added to a formulation and cannot be present in anyamount greater than about 1% w/w.

While not limiting the scope of express exclusion of the precedingparagraph, particular embodiments disclosed herein can be substantiallyfree of one or more of bimatoprost, carbomer, NaOH, TEA, ethanol,glycerin, diethylene glycol, monoethyl ether, propylene glycol,polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, PPG-5ceteth-20, oleic acid, isostearyl isostearate, isopropyl myristate,dipropylene glycol dimethyl ether, diethylene glycol, dipropyleneglycol, triglycerides, caprylic/capric, benzyl alcohol, silicone andwater.

All components of formulations described herein will be included inamounts that are dermatologically-acceptable. As used herein,“dermatologically-acceptable” means that the compositions or componentsthereof are suitable for use in contact with human skin without unduetoxicity, incompatibility, instability, allergic response, and the like.As used in herein as applied to active agents and excipients, the term“about” refers to variations in concentrations which are considered tobe bioequivalent.

Embodiments disclosed herein find application in mammalian species,including both humans and animals. In humans, the compounds ofembodiments disclosed herein can be applied without limitation, to thescalp, face, beard, head, pubic area, upper lip, eyebrows, and eyelids.The compositions of the present inventions may be used for treatingvarious hair loss disorders including but not limited to alopeciaareata, telogen effluvium, anagen effluvium, cicatricial alopecia andscarring alopecia; hair shaft abnormalities such as trichorrexis nodosa,loose anagen syndrome, trichotillomania and traction alopecia;infectious hair disorders such as tiniea capitis, sebohorreicdermatitis, and follicullitus of the scalp; genetic disorders such asandrogenetic alopecia and patients undergoing hair loss due tochemotherapy, hormonal imbalance (e.g., thyroid conditions such ashypothyroidism and hyperthyroidism, pregnancy, child birth,discontinuation of birth control pills and changes in menstrual cycle),fungal infection of the scalp such as ringworm, medicines which causehair loss such as anti-coagulants, medicine for gout, depression, highblood pressure and certain heart medications. The formulations of thepresent invention may be used to treat hair loss related to otherdisease such as diabetes, lupus, and poor nutrition, mental and physicalstress such as due to surgery, illness and high fever. Environmentalfactors and chemicals used in hair treatment (dying, tinting andbleaching).

In animals raised for their pelts, e.g., mink, the formulations can beapplied over the entire surface of the body to improve the overall peltfor commercial reasons. The process can also be used for cosmeticreasons in animals, e.g., applied to the skin of dogs and cats havingbald patches due to mange or other diseases causing a degree ofalopecia.

The compositions and methods of the present invention may be applied topatients suffering from hair loss or in healthy patients simply wantingto increase hair growth in any part of the body.

The compositions disclosed herein are formulated for topicaladministration. The term “topical administration” as used hereinincludes applying a formulation as described herein to the outer skin orhair. The application will generally occur at or near the area ofdesired hair growth.

Accordingly, appropriate formulation or composition types include,without limitation, solutions, gels, ointments, foams, films, liniments,creams, shampoos, lotions, pastes, jellies, sprays and aerosols. Suchformulation types can be applied in swaths, patches, applicators orthrough the use of impregnated dressings depending on the situation andpart of the body to be treated.

Typically, the formulations described herein will be applied repeatedlyfor a sustained period of time to the part of the body to be treated. Inparticular embodiments, formulations disclosed herein can include one ormore applications daily, one or more applications weekly, one or moreapplications monthly or one or more applications yearly for a period oftreatment of at least one day, at least one week, at least one month, atleast one year or until the treatment has achieved or achieved andmaintained a desired result.

Formulations described herein will be administered in safe and effectiveamounts. As used herein, “safe and effective amounts” include an amountsufficient so that the composition provides the desired hair growthstimulation effect at a reasonable benefit/risk ratio attendant with anymedical treatment. Within the scope of sound medical judgment, theamount of active components used can vary with the particular conditionbeing treated, the severity of the condition, the cause of thecondition, the duration of the treatment, the specific active componentemployed, its concentration, the specific vehicle utilized, the generalhealth of the patient, the tolerance of the patient to various effectsof the administration, other drugs being administered to the patient,and like factors within the specific knowledge and expertise of thepatient or attending physician.

For daily administration, an appropriate dose can include, withoutlimitation, about 0.1 ng to about 100 mg, about 1 ng to about 10 mg perday or in another embodiment about 10 ng to about 1 mg per day.

Non-limiting examples of some components with their appropriateconcentration ranges and function are provided in Tables 1A and B below.Particular examples of non-limiting formulations or compositions areprovided in Table 2.

TABLE 1A Example Components with Function and Concentration RangesComposition Ingredient Function (% w/w) bimatoprost Active 0.03-1.0 carbomer Thickener 0.05-1.0  base Neutralizing Agent 0.01-2.0  ethanolPenetration enhancers 10-90 glycerin 1.0-20  diethylene glycol 1.0-50 monoethyl ether propylene glycol  1-50 polysorbate 20 0.1-5.0polysorbate 40 0.1-5.0 polysorbate 60 0.1-5.0 polysorbate 80 0.1-5.0PPG-5 ceteth-20 0.1-5.0 oleic acid 0.1-5.0 isostearyl isostearate0.1-10  isopropyl myristate 0.1-10  dipropylene glycol  1-50 dimethylether diethylene glycol  1-50 dipropylene glycol  1-50 caprylic/capric0.1-10  triglycerides benzyl alcohol Preservative 0.1-2.0 siliconeOcclusive Agent 0.1-10  water Vehicle  0-90

TABLE 1B Example Components with Function and Concentration RangesComposition Ingredient Function (% w/w) bimatoprost Active 0.03-1.0 carbomer Thickener 0.05-1.0  base Neutralizing Agent 0.01-2.0  ethanolPenetration enhancers 10-90 glycerin 1.0-20  diethylene glycol 1.0-50 monoethyl ether propylene glycol  1-50 polysorbate 20 0.1-5.0polysorbate 40 0.1-5.0 polysorbate 60 0.1-5.0 polysorbate 80 0.1-5.0PPG-5 ceteth-20 0.1-5.0 oleic acid 0.1-5.0 isostearyl isostearate0.1-10  isopropyl myristate 0.1-10  dipropylene glycol  1-50 dimethylether diethylene glycol  1-50 dipropylene glycol  1-50 caprylic/capric0.1-10  triglycerides oleyl alcohol 0.1-10  benzyl alcohol Preservative0.1-2.0 silicone Occlusive Agent 0.1-10  water Vehicle  0-90

TABLE 2 Example Compositions Ingredient Function Composition (% w/w)bimatoprost Active 0.1 0.1 0.1 0.1 0.1 0.1 0.1 carbomer Thickener 0.100.15 0.125 0.10 0.20 0.25 0.25 NaOH (s) Neutralizing 0.035 Agent TEANeutralizing 0.22 0.18 0.15 0.22 0.38 0.38 Agent ethanol Penetration15.0 15.0 30.0 30.0 60.0 60.0 50.0 glycerin enhancers 5.0 diethyleneglycol 10.0 10.0 20.0 10 monoethyl ether propylene glycol 20 polysorbate20 4.0 4.0 4.0 water Vehicle 74.8 70.5 49.595 49.7 34.48 35.27 35.27

Example 1: Preparations of Bimatoprost Scalp Hair Growth GelCompositions

Ethyl alcohol is weighed into a suitable media jar equipped for mixing,bimatoprost is then added to the ethyl alcohol and stirred at moderatespeed until bimatoprost is dissolved. Into separate mixing tank,glycerin, diethylene glycol monoethyl ether, and propylene glycol areadded and mixed until the solvents are dispersed. Ethylalcohol/bimatoprost solution is then added into the non-aqueous solutionand mixed until the components are homogenously mixed (about 5 minutesof mixing). To the above mixture the carbomer thickener previouslydispersed in water is added and mixed until well dispersed, oncedispersed a base is added to thicken the solution into a gel.Representative formulations made according to the method above are shownin Table 3 below.

TABLE 3 Bimatoprost Scalp Hair Growth Topical Gel FormulationsBimatoprost Bimatoprost Bimatoprost Bimatoprost 0.03% 0.1% 0.3% 0.2%(Propylene (Propylene (Propylene (Propylene Ingredient Glycol) Glycol)Glycol) Glycol) (% w/w) Solution Solution Solution Solution Bimatoprost0.03 0.1 0.3 0.2 Propylene 10.0 10.0 10.0 10.0 glycol Diethylene 10.010.0 10.0 10.0 glycol monoethyl ether Ethyl 30.0 30.0 30.0 30.0 alcoholGlycerin 2.0 2.0 2.0 2.0 Carbomer 0.15 0.15 0.15 0.15 (Ultrez 10)Trietha- 0.16 0.16 0.16 0.16 nolamine Purified 47.66 47.59 47.39 47.49water

Example 2: In Vivo Treatment

A study is initiated to systematically evaluate the appearance of hairon the scalp and eyebrows who are administered bimatoprost gelformulations as in Table 3. The study involves 10 subjects, 5 male, 5female, average age 70 years, (ranging from 50-94 years). Each subjectis treated daily by the topical application of bimatoprost by the 0.3%w/w bimatoprost formulation of Table 3.

The study is limited to subjects who have administered bimatoprost formore than 3 months. The mean duration of exposure to the 0.3% w/wbimatoprost gel formulation prior to assessing the parameter of hair oreyebrow growth between the control and study eye is 129 days (range90-254 days). Observations are made under high magnification at a slitlamp biomicroscope. Documentation of differences between the control andtreatment areas is accomplished using a camera specially adapted for usewith a slit lamp biomicroscope.

The Results of the Observations Will be as Follows:

Length of hair and eyebrows: Increased length of hair in both groups isregularly observed. The difference in length varies from approximately10% to as much as 30%.

Number of hairs and eyebrows: Increased numbers of hairs are observed onthe scalp and eyebrows of each patient. The difference in number of hairand eyebrows varies from approximately 5% to as much as 30%. Whetherstatistically significant or not, bimatoprost with a penetrationenhancer will provide better and/or faster results than bimatoprostwithout a penetration enhancer.

The foregoing observations will establish that 0.03% w/w bimatoprostcomposition penetrates skin and grows hair.

Example 3: Topical Cream

A topical 0.2% w/w bimatoprost cream is prepared as follows: Tegacid andspermaceti are melted together at a temperature of 70-80° C.Methylparaben is dissolved in about 500 gm of water and propyleneglycol, polysorbate 80, bimatoprost and a penetration enhancer are addedin turn, maintaining a temperature of 75-80° C. The methylparabenmixture is added slowly to the Tegacid and spermaceti melt, withconstant stirring. The addition is continued for at least 30 minuteswith additional stirring until the temperature has dropped to 40-45° C.Finally, sufficient water is added to bring the final weight to 1000 gmand the preparation stirred to maintain homogeneity until cooled andcongealed.

Example 4: Topical Cream

A 0.1% w/w bimatoprost topical cream is prepared as follows: Tegacid andspermaceti are melted together at a temperature of 70-80° C.Methylparaben is dissolved in water and propylene glycol, polysorbate80, bimatoprost and a penetration enhancer are added in turn,maintaining a temperature of 75-80° C. The methylparaben mixture isadded slowly to the Tegacid and spermaceti melt, with constant stirring.The addition is continued for at least 30 minutes with additionalstirring until the temperature has dropped to 40-45° C. Finally,sufficient water is added to bring the final weight to 1000 gm and thepreparation stirred to maintain homogeneity until cooled and congealed.

Example 5: Topical Ointment

An Ointment Containing 2.0% w/w Bimatoprost is Prepared as Follows:

White petrolatum and wool fat are melted, strained and liquid petrolatumis added thereto. Bimatoprost, a penetration enhancer, zinc oxide, andcalamine are added to the remaining liquid petrolatum and the mixturemilled until the powders are finely divided and uniformly dispersed. Themixture is stirred into the white petrolatum, melted and cooled withstirring until the ointment congeals. In other variants, the zinc oxideand/or calamine can be omitted such that the formulation issubstantially free of the zinc oxide or calamine.

Example 6: Ointment

An ointment containing 5% w/w bimatoprost and a penetration enhancer isprepared by adding the active compound to light liquid petrolatum. Whitepetrolatum is melted together with wool fat, strained, and thetemperature adjusted to 45-50° C. The liquid petrolatum slurry is addedand the ointment stirred until congealed. The ointment can be packagedin 30 gm tubes.

Example 7: Spray Formulation

An aqueous spray formulation containing 0.03%, w/w bimatoprost and apenetration enhancer are prepared as follows. Bimatoprost and apenetration enhancer are dissolved in water and the resulting solutionis sterilized by filtration. The solution is aseptically filled intosterile containers with a spray nozzle for application on top of thehead. The formulation is presented in Table 4A below. An alternativeformulation is also listed in Table 4B.

TABLE 4A Bimatoprost Spray Formulation of Example 7 Spray formulationIngredient (% w/w) (w/w %) Bimatoprost 0.03 Propylene glycol 5Diethylene glycol monoethyl ether 5 Ethyl alcohol 15 Light mineral oil —Ceteareth 12 — Glycerin 1 Carbomer (Ultrez 10) — Triethanolamine —Purified water 24 Hydrofluoro carbon, hydrocarbon 49.97 propellant, CO₂,or, Nitrogen

TABLE 4B Alternative bimatoprost Spray Formulation Spray formulationIngredient (% w/w) (w/w %) Bimatoprost 0.03 Propylene glycol 5Diethylene glycol monoethyl ether 5 Ethyl alcohol 15 Glycerin 1 PVP orCellulose 0.1-1% Purified water 24 Hydrofluoro carbon, hydrocarbon 49.97propellant, CO₂, or, Nitrogen

Example 8: Lotion

A sample of bimatoprost and a penetration enhancer is dissolved in thevehicle of N-methyl pyrrolidone and propylene glycol to make a 0.5% w/wbimatoprost lotion for application to the scalp or other parts of thebody for growing hair.

Example 9: Aerosol

An aerosol containing approximately 0.1% w/w bimatoprost and apenetration enhancer is prepared by dissolving the bimatoprost and apenetration enhancer in absolute alcohol. The resulting solution isfiltered to remove particles and lint. This solution is chilled to about−30° C. A chilled mixture of dichlorodifluoromethane anddichlorotetrafluoroethane is then added to the solution. Thirteen mlplastic-coated amber bottles can be cold filled with 11.5 gm each of theresulting solution and capped. The aerosol may be sprayed onto the scalpor other parts of the body to grow hair.

Example 10: Topical Foam Formulation

A 0.1% w/w bimatoprost topical foam formulation is prepared as follows:Methylparaben is dissolved in about 500 gm of water and propyleneglycol, polysorbate 80, bimatoprost and a penetration enhancer are addedin turn, maintaining a temperature of 75-80° C. The methylparabenmixture is added slowly to Tegacid and spermaceti, with constantstirring. The addition is continued for at least 30 minutes withadditional stirring until the temperature has dropped to 40-45° C.Finally, sufficient water is added to bring the final weight to 1000 gmand the preparation stirred to maintain homogeneity until cooled andcongealed.

Alternative foam formulations prepared in a similar manner as taught inExample 10 are described below in Tables 5A-B.

TABLE 5A Foam formulation Ingredient (% w/w) (w/w %) Bimatoprost 0.03Propylene glycol — Diethylene glycol monoethyl ether 5 Ethyl alcohol 10Light mineral oil 6 Ceteareth 12 5 Glycerin — Carbomer (Ultrez 10) —

TABLE 5B Foam formulation Ingredient (% w/w) (w/w %) Bimatoprost 0.03Propylene glycol — Diethylene glycol monoethyl ether 5 Ethyl alcohol 10Light mineral oil 6 Myrj 45 5 Glycerin —

Example 11: Dusting Powder

A powder of the compound bimatoprost and a penetration enhancer isprepared by mixing in dry form with talcum powder at a weight/weightratio of 1:1:10.

Example 12: Related Compounds

Following the procedures of the preceding Examples, compositions aresimilarly prepared substituting an equimolar amount of a compound ofTable 1A for the bimatoprost disclosed in the preceding Examples.

Unless otherwise indicated, all numbers expressing quantities ofingredients, properties such as molecular weight, reaction conditions,etc. used in the specification and claims are to be understood as beingmodified in all instances by the term “about.” “About” refers tovariations in concentrations of excipients and types of excipients whichare considered to be bioequivalent according to the FDA and otherregulatory authorities.

Example 13

A 44 year old Caucasian male undergoing hair loss due to alopecia areataapplies once daily before sleeping the 0.1% w/w bimatoprost compositionof Table 3 for a period of 6 months. After 3 months of application, thesubject will notice new hair growth where there previously had been noneand darkening of the follicles of old hair. Observations of new hairgrowth are made under high magnification at the slit lamp biomicroscopeand by computer assisted image analysis. Documentation of differencesbetween the control and treatment areas is accomplished using a cameraspecially adapted for use with the slit lamp biomicroscope.

Example 14

A 37 year old Hispanic male suffering from male pattern baldness due toandrogenetic alopecia applies the 0.2% w/w bimatoprost composition ofTable 3 twice daily in areas where hair is noticeably thinning. After 63days of application, increased growth of hair will be noticed as will benew hair growth as measured by high magnification at the slit lampbiomicroscope and by computer assisted image analysis. Aftersatisfactory levels of hair growth are observed, the patient applies the0.2% w/w bimatoprost composition only twice a week.

Example 15

A 29 year old Caucasian healthy female wishes to have fuller hair andmore hair growth even though no disease or hair loss condition has beendiagnosed by doctors. The patient will apply the 0.3% w/w bimatoprostcomposition of Table 3 once daily until more hair growth is observedafter approximately three months of use. The patient continues to applythe composition once a week to maintain the increased hair growth.

Example 16

A 35 year old African American male diagnosed with folliculardegeneration syndrome and associated hair loss will apply the 0.03% w/wbimatoprost composition of Table 3. The composition will be appliedtwice daily, once in the morning after showering and once in theevening. After 46 days of application, increased hair growth will benoticed and easing of the symptoms of follicular degeneration syndrome.The patient continues application for another 6 months.

Further examples of formulations containing bimatoprost are alsopossible, and may be used to further stimulate hair growth. In someembodiments, some formulations may be particularly beneficial tostimulate hair growth in the scalp.

Example 17: Bimatoprost Solution Formulation with Oleyl Alcohol

A formulation of bimatoprost solution containing 0.3% w/w bimatoprostand a penetration enhancer comprising oleyl alcohol may be prepared asfollows. The ingredients of Table 7 below are weighed and dispensed intoa suitable media jar equipped for mixing. Preferably, bimatoprost isdissolved into the ethanol, and then combined with oleyl alcohol,propylene glycol and water. The various components are mixed togetheruntil homogenously mixed. It will be understood that the formulationprovided in Table 7 is non limiting and that other formulations are ofcourse possible and envisioned. The bimatoprost solution below had aratio of bimatoprost to oleyl alcohol of 0.06, a ratio of bimatoprost toethanol of 0.005, and a ratio of oleyl alcohol to ethanol of 0.083.

TABLE 7 bimatoprost solution formulation with oleyl alcohol Ingredient(% w/w) Bimatoprost solution Bimatoprost 0.3 Oleyl Alcohol 5 Ethanol 60Propylene glycol 20 Purified water 14.97

Example 18: Bimatoprost Solution Formulation without Oleyl Alcohol

Of course, while the example above comprises oleyl alcohol, which isbelieved to act as a penetration enhancer, some compositions maynevertheless not comprise this compound. Table 8 below illustratesadditional non-limiting examples of such formulations. The bimatoprostsolutions 8A and 8B below had a ratio of bimatoprost to ethanol of0.005.

TABLE 8 bimatoprost solution formulation with oleyl alcohol IngredientBimatoprost Bimatoprost (% w/w) solution 8A solution 8B Bimatoprost 0.30.3 Ethanol 60 60 Propylene glycol 20 0 Transcutol ® 0 20 Benzyl Alcohol0 2.5 Purified water 19.97 17.47

In the preceding and throughout, Transcutol® refers to a commercialproduct sold by Gattefossé, and which comprises diethylene glycolmonoethyl ether.

Example 19: Bimatoprost Gel Formulation without Oleyl Alcohol

In addition to the gel formulation provided in Example 1 above, a gelformulation comprising 0.3% w/w bimatoprost may also be manufacturedusing the ingredients listed in Table 9 below.

The ingredients in Table 9 are formulated into a gel according to thefollowing procedure. First, ascorbic acid and EDTA are dissolved in aportion of the total water. Then, carbopol 974P is added to thissolution to disperse and wet the carbopol. Next, poloxamer 407 is addedto another portion of the total water in a separate container and mixedto disperse. The carbopol portion is then added to this part and mixed.Polysorbate 80, hexylene glycol and PEG 400 are next combined in anothercontainer and mixed until homogeneous. BHA, BHT and bimatoprost areweighed into another container, followed by the addition of benzylalcohol. The ingredients are mixed together until homogeneous.Subsequently, this part is added to the Polysorbate 80 part and mixed.All parts are mixed together, followed by mixing in the remaining waterand tromethamine (which have been previously mixed together) so as toneutralize the gel

TABLE 9 bimatoprost gel formulation Ingredient (% w/w) Bimatoprost GelBimatoprost 0.3 Benzyl alcohol 1 Tromethamine 0.8 Hexylene Glycol 2 PEG400 45 Carbomer (Ultrez 10) 1.25 Poloxamer 407 0.2 Polysorbate 40 0.2Ascorbic Acid 0.5 BHT 0.5 BHA 0.5 EDTA 0.5 Purified water 47.66

Example 20: In Vitro Testing

The formulations described in Tables 7, 8, and 9 above were tested withan in vitro system comprising a 1.0 cm² Franz Cell diffusion chamber.During this testing, the Franz Cell comprises a sample of dermatomizedex-vivo human cadaver posterior trunk skin overlaying a diffusion cellfilled with receptor solution fluid configured to simulate body fluid.

The tested formulations were applied to the skin samples overlaying thediffusion cell. Two donor cadavers were used, the first from a 43-yearold black male, and the second from a 59-year old white male. Testingwas performed in triplicate for each donor and formulation tested. Tenμl of tested solution was applied per square centimeter of skin. At 2,4, 7, 24, and 48 hour intervals, receptor solution fluid was collectedat each time point, and the amount of bimatoprost was quantified. Toobtain the cumulative receptor solution concentration, the amount ofbimatoprost calculated at each time interval above were added together.Analysis and bimatoprost quantification for the skin stratum corneum anddermis was performed at the 48 hour endpoint.

TABLE 10 Summary of in vitro skin penetration results CumulativeReceptor Stratum Corneum and Solution Fluid Epidermis Conc. at 48 DermisConc. at 48 Concentration at 48 Formulation hrs. (ng bimatoprost) hrs.(ng bimatoprost) hrs. (ng. bimatoprost) Bimatoprost 0.3% 700 18.8 6.95(Propylene Glycol) Solution, Table 3 Bimatoprost solution, 1600 164 2390Table 7 Bimatoprost solution 8A, 410 41.3 28.9 Table 8 Bimatoprostsolution 8B, 200 51.4 30.2 Table 8 Bimatoprost gel, Table 9 64 14.2 BLQ

As shown in Table 10 above, the 0.3% bimatoprost formulation describedin Table 3 was compared to the new formulations of Tables 7, 8, and 9.The new formulations (all containing 0.3% bimatoprost) all exhibitedgreater cumulative amounts of bimatoprost permeating through the skinsample and into the receptor solution, with the exception of the gelformulation which exhibited minimal skin penetration. Unexpectedly, theformulation from table 7 that contained oleyl alcohol as a skinpenetrant showed a surprisingly higher skin penetration (stratumcorneum/epidermis and dermis concentration), and greater cumulativereceptor solution fluid concentration relative to the other testedformulations.

Example 21: Additional 1% and 3% Bimatoprost Formulations

Additional formulations were prepared in a similar manner to what hasalready been described. Table 11 illustrates examples of suchformulations, illustrating that the formulations do not necessarily needto comprise oleyl alcohol. The bimatoprost solution A below had a ratioof bimatoprost to ethanol of 0.03. The bimatoprost solution B had aratio of bimatoprost to ethanol of 0.01. The bimatoprost solution C hada ratio of bimatoprost to ethanol of 0.005. The bimatoprost solution Dhad a ratio of bimatoprost to ethanol of 0.0167. The bimatoprostsolution E had a ratio of bimatoprost to ethanol of 0.05.

TABLE 11 1% and 3% bimatoprost formulations Bimat- Bimat- Bimat- Bimat-Bimat- oprost oprost oprost oprost oprost solution solution solutionsolution solution Ingredient A B C D E (% w/w) 1% 3% 0.3% 1% 3%Bimatoprost 1 3 0.3 1 3 Transcutol ® 10 10 0 0 0 Ethanol 30 30 60 60 60Propylene 10 10 20 20 20 glycol Glycerin 2 2 0 0 0 Carbomer 0.15 0.15 00 0 (Ultrez 10) Triethanolamine 0.16 0.16 0 0 0 Purified water 46.6944.69 19.7 19 17

Example 22: In Vitro Testing

The formulations of Table 11 were compared to the Bimatoprost 0.3%Solution formulation of Table 3. Testing was done using the sameapparatus and general setup as Example 20 above. Here, however, thecadaver skin samples came from a 44 year old white female, and a 60 yearold white female.

TABLE 12 Summary of in vitro skin penetration results CumulativeReceptor Solution Fluid Dermis Conc. at 48 Concentration at 48Formulation hrs. (ng bimatoprost) hrs. (ng. bimatoprost) Bimatoprost0.3% 69.1 28.7 (Propylene Glycol) Solution, Table 3 Bimatoprost solutionA 35.3 58.3 1%, Table 11 Bimatoprost solution B 787 133 3%, Table 11Bimatoprost solution C 139 83.1 0.3%, Table 11 Bimatoprost solution D1060 175 1%, Table 11 Bimatoprost solution E 1410 230 3%, Table 11

The results above indicate that the bimatoprost formulations with ahigher relative ethanol and propylene glycol content, i.e., thesolutions C, D, and E from Table 10, showed higher receptor solution anddermis concentration relative to the other formulations.

Example 23: Additional Bimatoprost Formulations

Further formulations were also prepared using similar manufacturingtechniques as have been previously described. Here, the formulationsdescribed below in Table 13 were manufactured comprising oleyl alcoholas a skin penetrating agent. In table 13, bimatoprost solution A had aratio of bimatoprost to oleyl alcohol of 0.6, a ratio of bimatoprost toethanol of 0.045, and a ratio of oleyl alcohol to ethanol of 0.076. Thebimatoprost solution B had a ratio of bimatoprost to oleyl alcohol of0.6, a ratio of bimatoprost to ethanol of 0.05, and a ratio of oleylalcohol to ethanol of 0.083. The bimatoprost solution C had a ratio ofbimatoprost to oleyl alcohol of 0.6, a ratio of bimatoprost to ethanolof 0.05, and a ratio of oleyl alcohol to ethanol of 0.083.

TABLE 13 Additional bimatoprost formulations Bimatoprost BimatoprostBimatoprost Ingredient solution A solution B solution C (% w/w) 3% 3% 3%Bimatoprost 3 3 3 Oleyl alcohol 5 5 5 Ethanol 66 60 60 Propylene 22 2020 glycol Cremophor 0 5 0 RH40 (PEG 40 castor oil) Cremophor 0 0 8 ELP(PEG 35 castor oil) Purified water 4 7 4

Example 24: Additional Bimatoprost Gel Formulation

An additional gel formulation containing 10% w/w bimatoprost was alsoprepared using similar manufacturing techniques as have been previouslydescribed. The bimatoprost gel formulation below had a ratio ofbimatoprost to ethanol of 0.33. Table 14 below describes the specificingredients comprising this formulation.

TABLE 14 Additional bimatoprost gel formulation Ingredient (% w/w)Bimatoprost Gel Bimatoprost 10 Ethanol 30 Transcutol ® 10 PropyleneGlycol 10 Glycerin 2 Carbomer Ultrez 10 0.15 Triethanolamine 0.16Purified water 37.69

Example 25: In Vitro Testing

The formulations of Tables 13 and 14 were compared to the bimatoprost0.03% Solution formulation of Table 3. Testing was done using the sameapparatus and general setup as used in Examples 20 and 22 above. Here,the cadaver skin samples were from three donor cadavers—a 54 year oldwhite male, a 42 year old black male, and a 26 year old white male.

TABLE 15 Summary of in vitro skin penetration results CumulativeReceptor Solution Fluid Dermis Conc. at 48 Concentration at 48Formulation hrs. (ng bimatoprost) hrs. (ng. bimatoprost) Bimatoprost0.3% 79.1 250 (Propylene Glycol) Solution, Table 3 Bimatoprost solutionA 1970 17200 3%, Table 13 Bimatoprost solution B 1240 8100 3%, Table 13Bimatoprost solution C 2900 5640 3%, Table 13 Bimatoprost 10% gel 2820646 formulation, Table 14

Relative to the control formulation of Table 3, the 3% bimatoprostsolutions containing oleyl alcohol demonstrated high skin permeation andpermeation into the receptor solution. Solution A demonstrated aparticularly high receptor fluid concentration relative to the otheroleyl alcohol formulations.

Additionally, the 10% w/w bimatoprost gel formulation from Table 14,which did not include any oleyl alcohol, showed a high dermalconcentration, but did not exhibit as much penetration into the receptorsolution as the 3% w/w bimatoprost solutions. Nevertheless, the testedcharacteristics of all four new formulations were superior compared tothe original control formulation.

Example 26: Additional Bimatoprost Formulations

Examples of formulations containing bimatoprost and one or morepenetration enhancers may be found in Table 16 below, and weremanufactured in accordance with the techniques described previously.

TABLE 16 Additional 3% bimatoprost formulations Formulation # 1 2 3 4 56 7 Ingredient (% w/w) Bimatoprost 3 3 3 3 3 3 3 Water 2 2 2 6 4 QS QS100 100 cetostearyl 0.5 1 — — — — — alcohol glyceryl — — 2 2 2 — —mono-oleate Oleyl alcohol — — — — — 2 — Ethanol 73.5 73 72  68  68.2568.25 30 Propylene Glycol 10 10 10  10  22.75 22.75 10 Transcutol P 1010 10  10  — — 10 Benzyl alcohol 1 1 1 1 — — — Ultrez — — — — — — 0.15Trolamine — — — — — — 0.16 Glycerol — — — — — — 2

Example 27: Additional In Vitro Testing

The formulations from Table 16 above were tested in an in vitro skinpenetration testing method. Testing was done using the same apparatusand general setup as used in Examples 20 and 22 above.

TABLE 17 Summary of in vitro skin penetration results Cumulative amountin Dermis Formulation # (from receptor Concentration at Table 16)solution (ng) 48 hours. (ng) F-1 567 ± 722 278 ± 73  F-2 907 ± 554 861 ±395 F-3 2050 ± 660  685 ± 108 F-4 2740 ± 260  894 ± 615 F-5 3110 ± 230 819 ± 356 F-6 4080 ± 1640 1480 ± 980  F-7 365 ± 317 757 ± 123

Compared to the formulation F-7, formulations F-2 through F-6 were foundto have demonstrated comparable or higher bimatoprost permeation intothe receptor fluid. Also formulations F-2 through F-6 were shown to havea higher amount of bimatoprost in the dermis. Formulation F-6, whichcontains oleyl alcohol, had the highest bimatoprost concentration in thedermis and receptor solution, respectively.

Example 28: Additional Bimatoprost Formulations

Examples of formulations containing bimatoprost and one or morepenetration enhancers may be found in Table 18 below, and weremanufactured in accordance with the techniques described previously. Itwill be noted that the formulations F-1 and F-2 are the same as thoseshown in Table 11.

TABLE 18 Additional bimatoprost formulations Formulation # -1 -2 -3 -4-5 -6 -7 -8 -9 -10 Ingredient (% w/w) Bimatoprost 3 1 1 1 1 1 1 1 1 1Glycerin 2 2 2 2 Ethanol 30 30 69.4 69.4 70 46 45 69.4 69.4 69.4Transcutol 10 10 21.1 10 10 4 21.1 Propylene Glycol 10 10 23.1 10 10 423.1 23.1 Benzyl Alcohol 1 1 1 Carbomer Ultrez 10 0.15 0.15 0.2Triethanolamine 0.16 0.16 0.3 Oleyl Alcohol 0.5 0.5 Oleic Acid 0.5 2 2Glycerol 2 2 2 monooleate (GMO) Water 44.69 46.69 6 6 6 30 42.5 6 4.54.5

Example 29: Additional In Vitro Testing

The formulations from Table 18 above were tested in an in vitro skinpenetration testing method. Testing was done using the same apparatusand general setup as used in Examples 20 and 22 above.

TABLE 19 Additional in vitro testing Cumulative amount in Dermisreceptor Concentration at Description solution (ng) 48 hours. (ng) F-145.7 ± 6.5  449 ± 231 F-2 36.6 ± 36.3 132 ± 70  F-3 209 ± 41  618 ± 457F-4 104 ± 32  145 ± 126 F-5 328 ± 183 476 ± 56  F-6 178 ± 41  830 ± 25 F-7 66.7 ± 29.7 452 ± 6  F-8 66.0 ± 28.1 391 ± 227 F-9 193 ± 134 935 ±680 F-10 206 ± 155 229 ± 72 

Compared to the formulation F-1 (which has a 3% bimatoprostconcentration), formulations F-3 through F-10 have comparable or higherbimatoprost permeation into the receptor fluid while containingbimatoprost at a 1% concentration. Additionally, formulations F-3, andF-5 through F-10 demonstrate a higher amount of bimatoprost in thedermis versus formulation F-1. This study shows that glycerol monooleateand oleic acid, respectively, may be useful in enhancing the penetrationof bimatoprost into and through the skin in an in vitro study comparedto formulations F-1 and F-2.

Example 30: Additional Bimatoprost Formulations

Examples of formulations containing bimatoprost and one or morepenetration enhancers may be found in Table 20 below, and weremanufactured in accordance with the techniques described previously. Itwill be noted that the formulations F-1 and F-2 are the same as thoseshown in Table 11.

TABLE 20 Additional bimatoprost formulations Formulation 1 2 3 4 6 7 8 9Ingredient (% w/w) Bimatoprost 3 1 1 1 1 1 1 1 Glycerin 2 2 Ethanol 3030 69.4 68.25 68.25 68.25 68.25 68.25 Transcutol 10 10 Propylene Glycol10 10 23.1 22.75 22.75 22.75 22.75 22.75 Benzyl Alcohol Carbomer Ultrez10 0.15 0.15 Triethanolamine 0.16 0.16 Oleyl Alcohol 0.5 Oleic Acid 2GMO 2 2 Linoleic Acid 2 Sodium Lauryl 0.2 0.2 Sulfate Docusate Sodium0.2 Water 44.69 46.69 6 4 7.8 5.8 7.8 6

Example 31: Additional In Vitro Testing

The formulations from Table 20 above were tested in an in vitro skinpenetration testing method. Testing was done using the same apparatusand general setup as used in Examples 20 and 22 above.

TABLE 21 Additional in vitro testing Cumulative amount in Dermisreceptor Concentration at Formulation ID solution (ng) 48 hours (ng) F-142.7 ± 3.1  348 ± 57  F-2 55.3 ± 31.7 135 ± 54  F-3 594 ± 301 202 ± 35 F-4 1070 ± 530  514 ± 168 F-6 101 ± 58  387 ± 435 F-7 624 ± 394 331 ±156 F-8 171 ± 93  377 ± 204 F-9 936 ± 419 378 ± 62 

Compared to the formulation F-1, formulations F-3 through F-9 havecomparable or higher bimatoprost permeation into the receptor fluidwhile using a comparatively lower percentage of bimatoprost (VA versus3%). A combination of GMO and oleic acid (Formulation F-4) and linoleicacid (Formulation F-9), showed the highest permeation of bimatoprostinto the receptor solution.

Example 32: Additional Bimatoprost Formulations

Examples of formulations containing bimatoprost and one or morepenetration enhancers may be found in Table 22 below, and weremanufactured in accordance with the techniques described previously. Itwill be noted that the formulation F-1 is the same as those shown inTable 11.

TABLE 22 Additional bimatoprost formulations Formulation 1 2 3 4 5 6 7 89 Ingredient (% w/w) Bimatoprost 3 1 1 1 1 1 1 1 1 Glycerin 2 Ethanol 3068.25 68.25 68.25 68.25 68.25 68.25 68.25 67 Transcutol 10 10 PropyleneGlycol 10 22.75 22.75 22.75 22.75 22.75 22.75 22.75 10 Benzyl Alcohol 1Oleic Acid 2 2 2 2 2 2 2 2 glycerol monooleate 2 2 2 2 2 2 2 2 LinoleicAcid 2 Terpinolene 2 Limonene 2 Nerol 2 Cineol 2 Octyl Salicylate 2 DMSO2 Carbomer Ultrez 10 0.15 triethylamine 0.16 Water 44.69 2 2 2 2 2 2 2 7

Example 33: Additional In Vitro Testing

The formulations from Table 22 above were tested in an in vitro skinpenetration testing method. Testing was done using the same apparatusand general setup as used in Examples 20 and 22 above.

TABLE 23 Additional in vitro testing Cumulative amount in Dermisreceptor Concentration at Formulation ID solution (ng) 48 hours (ng) F-110.5 ± 2.1  72 ± 27 F-2 1360 ± 360  581 ± 360 F-3 2030 ± 2170 183 ± 107F-4 5200 ± 2720 251 ± 172 F-5 3570 ± 1100 538 ± 583 F-6 4650 ± 1010 362± 163 F-7 5890 ± 4150 678 ± 644 F-8 6810 ± 1020 632 ± 314 F-9 3640 ±2020 279 ± 48 

Compared to the formulation F-1, formulations F-2 through F-9 havedemonstrated comparable or higher bimatoprost permeation into receptorsolution and into the dermis, even with a lower overall concentration ofbimatoprost.

Example 34: Additional Bimatoprost Formulations

Examples of formulations containing bimatoprost and one or morepenetration enhancers may be found in Table 24 below, and weremanufactured in accordance with the techniques described previously. Itwill be noted that the formulation F-1 is the same as those shown inTable 11.

TABLE 24 Additional bimatoprost formulations Formulation 1 2 3 4 5 6 7 89 Ingredient (% w/w) Bimatoprost 3 1 1 1 1 1 1 1 0.5 Glycerin 2 Ethanol30 46 68.25 68.25 68.25 68.25 68.25 10 Transcutol 10 10 Propylene Glycol10 10 22.75 22.75 22.75 22.75 22.75 Benzyl Alcohol 1 Oleic Acid 2 0.83.2 2 2 GMO 2 3.2 0.8 2 2 Sodium Lauryl 0.2 0.2 Sulfate DDAB 0.2 Sodium2 Taurodeoxycholate Docusate Sodium 0.2 Polysorbate 80 2 Crodamol MM 25Dow ST-Elastomer 10 73.5 Dow Silky Wax 10 8 Isopropyl Myristate 8Carbomer Ultrez 10 0.15 Trolamine 0.16 Water QS QS QS QS QS QS QS QS

Example 35: Additional Bimatoprost Formulations

In some embodiments, several possible formulations capable of superiorskin penetration may be manufactured as set forth in the two followingtables. Using a base formulation set forth in Table 25, a mixture of oneor more fatty acids or fatty esters (as set forth in Table 26) may beadded thereto. Preferably, a base formulation from Table 25 will becombined with at least two ingredients from Table 26. Even morepreferably, the at least two ingredients from Table 26 are one fattyacid and one fatty ester. Of course, it will be understood that theseformulations do not presume any particular order of manufacture, and areonly presented thusly for ease of understanding. While the baseformulations may be prepared with any appropriate concentration ofbimatoprost, this concentration is preferably between about 0.3% w/w andabout 5% w/w, more preferably about 1% w/w to about 3% w/w, and evenmore preferably about 3% w/w.

TABLE 25 Base formulations Composition Function Ingredient (% w/w)Active Ingredient Bimatoprost 0.3-5%  Excipients Ethanol 0-89 Propyleneglycol 0-89 Diethylene glycol 0-89 monoethyl ether Benzyl alcohol 0-89Water 0-89

TABLE 26 Example fatty acid and fatty ester excipients CompositionIngredient Example (% w/w) Fatty acids (C₈-C₂₈) Saturated stearic acid0-10 Monounsaturated oleic acid 0-10 Polyunsaturated linoleic acid 0-10Fatty esters (C₈-C₂₈) Saturated glyceryl monostearate 0-10Monounsaturated glyceryl monooleate 0-10 Polyunsaturated ethyl ester oflinoleic acid 0-10

Example 35: Clinical Testing to Evaluate the Efficacy and Safety ofOnce-Daily Topical Bimatoprost Solution for Increasing Scalp Hair Growthin Men with Androgenic Alopecia

In a phase 2 multicenter trial, men 18-49 years of age with mild tomoderate androgenic alopecia (AGA) were randomized in a 1:1:1:1:1 ratioto receive in a double-blind manner bimatoprost (BIM) 0.3%, 0.1%, 0.03%,or vehicle applied once daily, or open label over-the-counter minoxidil5% solution (MIN) applied twice daily to the vertex area of the scalpfor 6 months. Subjects were evaluated every 2 months during treatmentand at 2 months after completing treatment. The BIM formulations used inthis study were as described in Table 3 above.

The following assessments were made with digital image analysis (DIA;macrophotographs of a prespecified 1-cm² circular area at the anteriorleading edge of the vertex thinning area of the scalp identified bymicrodot tattoo) using customized validated software: Target Area HairCount (TAHC) measured in terminal hairs/cm²; Target Area Hair Width(TAHW) measured in mm/cm²; and, Target Area Hair Darkness (TAHD)measured in intensity units;

Other assessments included Subject Self Assessment (SSA), InvestigatorGlobal Assessment (IGA), and Global Panel Review (GPR) by an independentpanel of 3 dermatologists while viewing standardized global photographsof the scalp at baseline (day 1) and at the current visit (or liveassessment at the current visit in the case of IGA) Change in scalp hairgrowth was measured on 7-point ordinal scale from −3 (greatly decreased)to +3 (greatly increased).

Co-primary efficacy endpoints measured included the change from baselinein TAHC and the SSA of change in scalp hair growth. Secondary efficacyendpoints included changes from baseline in TAHW and TAHD, and IGA/GPRof changes in scalp hair growth.

Safety measures included adverse event monitoring, local tolerabilityassessment, clinical laboratory testing, vital signs, 12-leadelectrocardiograms (ECGs), and physical examinations.

Statistical efficacy analyses were performed on the modifiedintent-to-treat population, which included all randomized subjects whoreceived study treatment and had baseline measurements The co-primaryefficacy analyses were conducted at month 6. Percent changes frombaseline in TAHC, TAHW, and TAHD were analyzed using the Wilcoxonrank-sum test. Frequency distributions of SSA, IGA, and GPR scores wereanalyzed using a Cochran-Mantel-Haenszel test stratified for age group(18-34 vs 35-49 years), and missing data were imputed to month 6 using alast-observation-carried-forward approach. Safety measures wereevaluated in all subjects who received study medication; among-group andpairwise comparisons of the incidence of adverse events were performedusing a chi-square or Fisher's exact test

Results

A total of 307 men with AGA received study treatment and were includedin the efficacy and safety analyses. Treatment arms were generally wellbalanced with respect to demographic and baseline characteristics

Digital image analysis (DIA) showed that bimatoprost 0.3% produced asignificantly greater mean percentage change from baseline to month 6 inTAHC compared with vehicle (11.1% vs 3.3%; P=0.008). DIA also revealed asignificant improvement in TAHW, but not in TAHD, with bimatoprost 0.3%in comparison to the vehicle at month 6; significant improvements werealso seen at month 4 for TAHW. Two months after stopping treatment, thechanges in TAHC and TAHW with bimatoprost were no longer significantlydifferent from vehicle.

The distribution of SSA scores at month 6 did not differ betweenbimatoprost and vehicle. GPR assessments at month 6, but not IGAassessments, showed that the percentage of subjects with ≥1-gradeimprovement (i.e., scores of +3, +2, or +1) was significantly greaterwith bimatoprost 0.3% compared with vehicle (21.1% vs 8.9%; P=0.030).The improvement in GPR assessment with bimatoprost 0.3% was maintainedat 2 months post-treatment (16.4% vs 0%; P=0.017)

In the open-label minoxidil 5% treatment arm with twice-dailyapplication, treatment resulted in an increase in TAHC of 18.4% frombaseline at month 6. This was higher than published reports of an ≈13%increase in TAHC after 4 and 12 months of treatment. A majority ofsubjects (67.3%) on minoxidil 5% indicated 1-grade improvement in hairgrowth. At the doses tested, the efficacy of any bimatoprost group wasless than that of the MIN group

With reference to Table 27 below, the incidence of treatment-relatedadverse events was slightly higher with bimatoprost compared withvehicle, but lower than the rate with minoxidil.

TABLE 27 Summary of Treatment-Related Adverse Events (AEs) BimatoprostBimatoprost Bimatoprost Minoxidil Incidence, n Vehicle 0.03% 0.1% 0.3%5% (%) (n = 62) (n = 62) (n = 61) (n = 61) (n = 61) Subjects with ≥1 3(4.8) 3 (4.8) 7 (11.5) 5 (8.2) 13 (21.3) treatment-related AEs Mostcommon treatment-related AEs (reported by ≥2% ofsubjects in any group)Application- 1 (1.6) 0 0 2 (3.3) 2 (3.3) site dryness Application- 0 0 4(6.6) 1 (1.6) 7 (11.5) site pruritus Application- 0 0 3 (4.9) 1 (1.6) 2(3.3) site pain

With reference to Table 28 below, the most common dermal tolerabilitysymptoms were itching based on subject report and dryness/scaling basedon dermatologist report; both were less frequent with bimatoprost 0.3%compared with minoxidil. However, folliculitis was more common withbimatoprost 0.3% than with minoxidil on the dermatologist report.

TABLE 28 Dermal Tolerability Based on Subject and Dermatologist ReportsSubjects With ≥1 Severity Grade Increase From Bimatoprost BimatoprostBimatoprost Minoxidil Baseline at Vehicle 0.03% 0.1% 0.3% 5% Any Visit,n (%) (n = 62) (n = 62) (n = 61) (n = 61) (n = 61) Subject assessmentBurning 0 1 (1.6) 3 (4.9) 5 (8.2)* 3 (4.9) Itching 2 (3.2) 2 (3.2) 3(4.9) 7 (11.5) 14 (23.0)^(†) Stinging 0 1 (1.6) 2 (3.3) 5 (8.2)* 2 (3.3)Dermatologist assessment Dryness/scaling 8 (12.9) 9 (14.5) 7 (11.5) 9(14.8) 20 (32.8)^(‡) Erythema 4 (6.5) 5 (8.1) 7 (11.5) 9 (14.8) 7 (11.5)Edema 0 0 1 (1.6) 2 (3.3) 3 (4.9) Pigmentation 0 1 (1.6) 2 (3.3) 2 (3.3)3 (4.9) Folliculitis 0 3 (4.8) 2 (3.3) 8 (13.1)^(§) 2 (3.3) *P = 0.028;^(†)P = 0.001; ^(‡)P = 0.01; ^(§)P = 0.003 versus vehicle.

There were no clinically meaningful or dose-dependent changes inclinical laboratory parameters, vital signs, ECGs, or physicalexaminations with bimatoprost

CONCLUSIONS

The study demonstrated that topical bimatoprost 0.3% applied once dailysignificantly increased scalp hair growth compared with vehicle insubjects with mild-to-moderate AGA. Topical Minoxidil 5% applied twicedaily in an open-label manner showed efficacy higher than any of thebimatoprost doses tested. Topical bimatoprost exhibited a safety andtolerability profile that was consistent with that of an establishedtopical treatment for scalp hair growth

While the above detailed description has shown, described, and pointedout novel features as applied to various embodiments, it will beunderstood that various omissions, substitutions, and changes in theform and details of the device or process illustrated may be madewithout departing from the spirit of the disclosure. Additionally, thevarious features and processes described above may be used independentlyof one another, or may be combined in various ways. All possiblecombinations and subcombinations are intended to fall within the scopeof this disclosure. Many of the embodiments described above includesimilar components, and as such, these similar components can beinterchanged in different embodiments. Although the invention has beendisclosed in the context of certain embodiments and examples, it will beunderstood by those skilled in the art that the invention extends beyondthe specifically disclosed embodiments to other alternative embodimentsand/or uses and obvious modifications and equivalents thereof.Accordingly, the invention is not intended to be limited by the specificdisclosures of preferred embodiments herein.

What is claimed is:
 1. A composition for growing hair by topicalapplication comprising: bimatoprost in free form or a pharmaceuticallyacceptable salt thereof, wherein the bimatoprost is contained in anamount of about 0.3% w/w to about 4% w/w; at least one first compoundselected from a fatty acid, fatty acid alcohol and fatty ester, whereinsaid composition is formulated for topical administration to the skin.2. The composition of claim 1, wherein the first compound is a fattyacid.
 3. The composition of claim 2, wherein the fatty acid issaturated.
 4. The composition of claim 2, wherein the fatty acid isunsaturated.
 5. The composition of claim 2, wherein the fatty acid isselected from the group consisting of stearic acid, oleic acid, linoleicacid, and mixtures thereof.
 6. The composition of claim 1, wherein thefirst compound is a fatty ester.
 7. The composition of claim 6, whereinthe fatty ester is saturated.
 8. The composition of claim 6, wherein thefatty ester is unsaturated.
 9. The composition of claim 6, wherein thefatty ester is selected from the group consisting of glycerylmonostearate, glyceryl monooleate, and ethyl ester of linoleic acid. 10.The composition of any preceding claim, wherein the compositioncomprises at least two first compounds.
 11. The composition of claim 10,wherein the two first compounds comprise a mixture of at last one fattyacid and at least one fatty ester.
 12. The composition of any precedingclaim, wherein the first compound has 12-24 carbon atoms.
 13. Thecomposition of any preceding claim, further comprising at least onesecond compound selected from the group consisting of ethanol, propyleneglycol, diethylene glycol monoethyl ether, and benzyl alcohol.
 14. Thecomposition of any preceding claim, further comprising at least onethird compound selected from the group consisting of terpenes, occlusiveagents, surface active agents, sulfoxides, cyclic ethers, amides,amines, and dimethylaminopropionic acid derivatives.
 15. The compositionof claim 14, wherein the terpene is selected from the group consistingof terpinolene, limonene, nerol, and cineol.
 16. The composition ofclaim 14, wherein the occlusive agent is selected from the groupconsisting of silicones, mineral oils, and water insoluble polymers. 17.The composition of claim 14, wherein the surface active agent isselected from the group consisting of polysorbate 20, polysorbate 40,polysorbate 60, polysorbate 80, sodium dodecyl sulfate, sodium laurylsulfate, DMSO, and docusate sodium.
 18. The composition of claim 14,wherein the dimethylaminopropionic acid derivative is2-dimethylaminopropionic acid dodecyl ester.
 19. The composition of anypreceding claim, wherein the composition comprises bimatoprost in anamount of about 1% w/w to about 4% w/w.
 20. The composition of claim 19,wherein the composition comprises bimatoprost in an amount of about 2.5%w/w to about 3.5% w/w.
 21. The composition of claim 20, wherein thecomposition comprises bimatoprost in an amount of about 3% w/w.
 22. Thecomposition of any preceding claim, wherein the composition is in theform of one selected from the group consisting of solutions, gels,ointments, foams, films, liniments, creams, shampoos, lotions, pastes,jellies, sprays and aerosols.
 23. The composition of any precedingclaim, wherein the composition is packaged in a kit with an applicatorfor application to the skin.
 24. A method for stimulating hair growthcomprising administering to the skin of a patient an effective amount ofa bimatoprost composition according to any preceding claim, wherein theadministration causes increased hair growth.
 25. The method of claim 24,wherein the composition is applied to the scalp.
 26. The method of anyof claims 24-25, wherein the composition is applied at least once daily.27. The method of any of claims 24-26, wherein the composition isapplied to the scalp for treatment of a condition selected from thegroup consisting of alopecia areata, telogen effluvium, anageneffluvium, cicatricial alopecia, scarring alopecia; hair shaftabnormalities, trichorrexis nodosa, loose anagen syndrome,trichotillomania, traction alopecia; infectious hair disorders, tinieacapitis, sebohorreic dermatitis, follicullitus of the scalp, andandrogenetic alopecia.
 28. The method of any of claims 24-27, whereinthe composition is applied to one or both of the scalp and the eyebrowsfor patients experiencing hair loss due to chemotherapy, hormonalimbalance, fungal infection of the scalp, anti-coagulants, medicine forgout, depression, high blood pressure and heart disease.
 29. Acomposition for promoting the growth of hair, the compositioncomprising: at least one penetration enhancer; and bimatoprost in freeform or a pharmaceutically acceptable salt thereof, wherein thebimatoprost is contained in an amount of about 1-4% w/w; wherein saidcomposition is formulated for topical administration to the skin. 30.The composition of claim 29, wherein the penetration enhancer isselected from one or more of the group consisting of alcohols, glycols,fatty acids, fatty esters, fatty ethers, occlusive agents, surfaceactive agents, dimethylaminoproprionic acid derivatives, terpenes,sulfoxides, cyclic ethers, amides, and amines.